PRODUCT INFORMATION ZAN-EXTRA

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1 PRODUCT INFORMATION ZAN-EXTRA NAME OF THE MEDICINE Non-proprietary Name Lercanidipine hydrochloride Enalapril maleate Chemical Structure Lercanidipine HCl 3,5-pyridinedicarboxylic acid, 1,4- dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-2-[(3,3- diphenylpropyl)methylamino]-1,1-dimethylethyl methyl ester hydrochloride. Molecular Wt: (Free base: 611.7) Enalapril maleate CH 3 CH 2 O C O N H CH 3 C O N COOH H C C COOH H COOH (2S)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]pyrrolidine-2-carboxylic acid (Z)-butenedioate Molecular Wt: CAS Number Lercanidipine HCl: Enalapril maleate: Zan-Extra PI Version 1 Page 1

2 DESCRIPTION Lercanidipine hydrochloride is a microcrystalline, odourless, citrine-coloured powder, readily soluble in chloroform and methanol, practically insoluble in water. Octanol:water partition coefficient (LogP): 6.4. Enalapril maleate is a white or almost white crystalline powder sparingly soluble in water, practically insoluble in dichloromethane, and freely soluble in methyl alcohol. It dissolves in dilute solutions of alkali hydroxides. A 1% solution in water has a ph of 2.4 to 2.9. Zan-Extra film-coated tablets are immediate release film-coated tablets for oral use containing lercanidipine hydrochloride 10 mg and enalapril maleate 10 mg (Zan-Extra 10/10), or lercanidipine hydrochloride 10 mg and enalapril maleate 20 mg (Zan-Extra 10/20). Zan-Extra film-coated tablets also contain the following excipients: Lactose, microcrystalline cellulose, sodium starch glycollate (Type A), povidone, sodium bicarbonate, magnesium stearate, hypromellose, titanium dioxide (E171), purified talc, macrogol Additionally Zan-Extra 10/20 film-coated tablets contain quinoline yellow aluminium lake (E104) and iron oxide yellow (E172). PHARMACOLOGY Zan-Extra 10/10 and Zan-Extra 10/20 are fixed combinations of the calcium channel blocker, lercanidipine, and the angiotensin converting enzyme inhibitor, enalapril. In Phase III clinical trials performed in patients not adequately controlled by lercanidipine or enalapril monotherapy, the combination produced an additive antihypertensive effect which reduced blood pressure to a greater extent than the individual components. Pharmacodynamics Lercanidipine is a calcium channel antagonist of the dihydropyridine group and inhibits the transmembrane influx of calcium into cardiac and smooth muscle. The mechanism of its antihypertensive action is due to a direct relaxant effect on vascular smooth muscle thus lowering total peripheral resistance. Lercanidipine has a prolonged antihypertensive activity because of its high membrane partition coefficient, and is devoid of negative inotropic effects due to its vascular selectivity. Vasodilatation induced by lercanidipine is gradual in onset so acute hypotension with reflex tachycardia has rarely been observed in hypertensive patients. The antihypertensive activity of lercanidipine is mainly due to its (S)-enantiomer. Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor, enalaprilat. The liver appears to be the main site for this conversion. Enalapril maleate is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L- proline. Angiotensin Converting Enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance angiotensin II. Enalaprilat inhibits ACE which results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release), and decreased aldosterone secretion. ACE is identical to kininase II. Thus enalaprilat may also block the degradation of bradykinin, a potent vasodepressor peptide. However the role that this plays in the therapeutic effects of enalapril remains to be elucidated. The mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, however enalapril is antihypertensive even in patients with low-renin hypertension. Administration of enalapril to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate. Zan-Extra PI Version 1 Page 2

3 Symptomatic postural hypotension is infrequent. In some patients the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of enalapril has not been associated with rapid increase in blood pressure. Effective inhibition of ACE activity usually occurs 2 to 4 hours after oral administration of an individual dose of enalapril. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by 4 to 6 hours after administration. The duration of effect is dose-related. However, at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours. In haemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril there was an increase in renal blood flow; glomerular filtration rate was unchanged. There was no evidence of sodium or water retention. However in patients with low pretreatment glomerular filtration rates, the rates were usually increased. In short term clinical studies in diabetic and non-diabetic patients with renal disease, decreases in albuminuria and urinary excretion of IgG and total urinary protein were seen after the administration of enalapril. Ethnic differences As with other ACE inhibitors, enalapril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population. Pharmacokinetics When lercanidipine and enalapril were administered concomitantly no pharmacokinetic interaction was observed. Lercanidipine Absorption and Bioavailability Lercanidipine is completely absorbed after oral administration and peak plasma levels occur about 1.5 to 3 hours after dosing. The two enantiomers of lercanidipine show a similar plasma level profile: The time to peak plasma concentration is the same, the peak plasma concentration and AUC are, on average, 1.2-fold higher for the (S)-enantiomer. No in vivo interconversion of enantiomers is observed. The absolute bioavailability of lercanidipine is about 10%, because of high first pass metabolism. The bioavailability increases 4-fold when lercanidipine is ingested up to 2 hours after a high fat meal, and about 2-fold when taken immediately after a carbohydrate-rich meal. Consequently lercanidipine should be taken at least 15 minutes before a meal. Distribution Distribution from plasma to tissues and organs is rapid and extensive. The degree of serum protein binding of lercanidipine exceeds 98%. Since plasma protein levels are reduced in patients with severe renal or hepatic dysfunction, the free fraction of the drug may be increased. Metabolism Lercanidipine is extensively metabolised by CYP3A4; no parent drug is found in the urine or the faeces. It is predominantly converted to inactive metabolites and about 50% of the dose is excreted in the urine. Zan-Extra PI Version 1 Page 3

4 Oral administration of lercanidipine leads to plasma levels not directly proportional to dosage (nonlinear kinetics). After 10, 20 or 40 mg, peak plasma concentrations observed were in the ratio 1:3:8 and areas under plasma concentration time curves in the ratio 1:4:18, suggesting a progressive saturation of first pass metabolism. So availability increases with dosage elevation. Excretion Elimination occurs essentially by biotransformation. The mean terminal elimination half-life of S- and R-lercanidipine enantiomers is 5.8 ± 2.5 and 7.7 ± 3.8 hours respectively. No accumulation was seen upon repeated administration. The therapeutic activity lasts for 24 hours because of its high binding to lipid membranes. Elderly, renal impairment and hepatic impairment In elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic impairment the pharmacokinetic behaviour of lercanidipine was shown to be similar to that observed in the general patient population; patients with severe renal dysfunction or dialysis-dependent patients showed higher levels (about 70%) of the drug. In patients with moderate to severe hepatic impairment, the systemic bioavailability of lercanidipine is likely to be increased since the drug is normally metabolised extensively in the liver. Enalapril Absorption Oral enalapril is rapidly absorbed with peak serum concentrations occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril tablets is approximately 60%, similar for the various doses in the therapeutic range. The absorption of oral enalapril is not influenced by the presence of food in the gastrointestinal tract. Following absorption, oral enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Peak concentration of enalaprilat occurs three to four hours after an oral dose of enalapril maleate. Distribution Approximately 50% of enalaprilat is bound to plasma proteins. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. In subjects with normal renal function, steady state serum concentrations of enalaprilat were achieved by the fourth day of administration of enalapril maleate. The plasma concentration time profile of enalaprilat was complex with several exponentials including a very prolonged terminal phase (t1/2 >30 hours). The effective half-life for accumulation of enalaprilat following multiple doses of oral enalapril maleate is eleven hours. Metabolism Except for conversion to enalaprilat, there is no evidence for significant metabolism of enalapril. The extent of hydrolysis of enalapril is similar for the various doses in the recommended therapeutic range. Excretion Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril (about 20%). Zan-Extra PI Version 1 Page 4

5 Renal Impairment The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance ml/min) steady state AUC of enalaprilat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance 30 ml/min) AUC was increased approximately 8-fold. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency and time to steady state is delayed (see Dosage and Administration). CLINICAL TRIALS Factorial study (CPL2-0008) In a multi-centre, randomised, double-blind, placebo-controlled, parallel group, factorial design study 663 patients with essential hypertension were randomised to receive an eight-week double-blind treatment with either placebo or an active treatment with enalapril maleate (5 or 10 mg), lercanidipine HCl (5, 10 or 20 mg), or one of six different combinations of both drugs. Primary efficacy endpoint was the change from baseline in trough sitting DBP (24±2h post-dose). Both ANCOVA and response surface analysis were performed. The 10 mg and 20 mg doses of lercanidipine HCl were significantly superior to placebo, as was the 10 mg dose of enalapril maleate, while the 5 mg dose of both monotherapies were not superior to placebo. All the six combinations of lercanidipine plus enalapril (including the low dose combinations) were superior to placebo. In the response surface analysis, the estimated mean change in SitDBP from baseline in the lercanidipine HCl 10 mg/enalapril maleate 10 mg group ( mm Hg, 95% CI ) was significantly different from the lercanidipine HCl 10 mg group (-8.23 mm Hg, 95% CI ) and it was close to significance when compared to the enalapril maleate 10 mg group (-8.78 mm Hg, 95% CI ). In addition, this combination had a similar reduction to that observed in the lercanidipine HCl 20 mg group (-9.88 mm Hg, 95% CI ). The normalization rate in the lercanidipine HCl 10 mg/ enalapril maleate 10 mg group (55%) was similar to that observed in the lercanidipine HCl 20 mg group (59%), whereas rates of 40% and 43% were observed in the lercanidipine HCl 10 mg and the enalapril maleate 10 mg groups, respectively. Treatment with this dose combination was well tolerated. The combination lercanidipine 10 mg/enalapril maleate 10 mg was therefore considered a reasonable alternative, both from the efficacy and the safety perspectives, to drug titration in patients not controlled by lercanidipine HCl 10 mg monotherapy. Its efficacy was then tested in the pivotal add-on trial in non-responders to lercanidipine HCl (CPL-0018). The efficacy of the 10 mg/10 mg strength in patients whose blood pressure is not adequately controlled by enalapril 10 mg alone has not been tested. The dose combination lercanidipine HCl 10 mg/enalapril maleate 20 mg was instead chosen to be tested in the pivotal study in non-responders to enalapril maleate (CPL-0019), even if not previously included in the factorial study, because 20 mg is the usual maintenance dose of enalapril maleate. The efficacy of the 10 mg/20 mg strength in comparison with both monotherapies and placebo was tested in study IT-CL The lowest effective dose has not been formally determined. Study IT-CL 0044 A double-blind, placebo-controlled, four-way balanced-design cross-over study, including patients aged years with a mean office SitSBP of mmhg and a daytime SBP 135 mmhg, was performed to evaluate whether combination therapy with lercanidipine and enalapril 10mg/20mg was more effective than either drug alone in reducing SBP in the elderly. Zan-Extra PI Version 1 Page 5

6 After a two week run-in period, during which previous medications were discontinued, each patient received the following four treatments in randomised order for four weeks each: lercanidipine 10 mg, enalapril 20 mg, the combination L10/E20 mg and placebo. 75 patients (40 males, mean age 66 yrs, office BP 168/92 mmhg, daytime SBP 151 mmhg) were randomised, 72 entered in the ITT analysis and 62 completed the study with 4 valid post-baseline ABPMs and entered in the primary analysis on the PP population. Administration of placebo, lercanidipine, enalapril and the combination was associated with mean 24- h SBP of 144, 137, 133 and 127 mmhg, respectively. All active treatments significantly reduced the mean 24-h SBP in comparison with placebo, but the combination L10/E20 mg was significantly more effective than lercanidipine 10 mg and enalapril 20 mg alone. Similarly, office SBP at trough was significantly more reduced with the combination (-16.9 mmhg) than with lercanidipine (-5.0 mmhg) or enalapril (-5.9 mmhg) monotherapies. A blood pressure < 140/90 mmhg was recorded in 18% of patients with lercanidipine, 19% with enalapril and 45% with L10/E20 mg. Combination therapy improved blood pressure control over monotherapies in the entire 24-hour period. Tolerability of the combination therapy was good and no serious adverse reactions occurred. Efficacy in non-responders to lercanidipine (CPL1-0018) In a randomised, double blind study with 337 patients (in ITT population) whose blood pressures were inadequately controlled (DBP 95 mmhg) after 4 weeks treatment with lercanidipine 10 mg, patients were randomised to receive combination lercanidipine 10 mg and enalapril 10 mg once daily or lercanidipine 10 mg monotherapy for 12 weeks. Primary efficacy endpoint was the change from baseline in trough SitDBP (24±2h post-dose). Secondary efficacy parameters included the change from baseline in trough SitSBP and the percent of patients normalised or responders. At end of study, patients who used combination therapy were found to have a significantly greater reduction in trough SitSBP and SitDBP compared with those on monotherapy (-7.7 +/ / / mmhg vs / / / mmhg respectively). The statistically significant difference between treatment groups (p< 0.001) for reduction of both SitSBP and SitDBP were evident from as early as week 2 and persisted throughout the treatment period. It is noteworthy that the difference between treatments was even greater on SitSBP (5.4 mmhg) than on SitDBP (2.8 mmhg). SBP is recognised as the most important predictor of stroke and coronary mortality across all ages. A significantly higher percentage of patients on combination treatment experienced normalization of SitDBP (29% vs. 19%, p=0.023), SSBP (39% vs. 22%, p<0.001) or both (22% vs. 12%, p=0.012) compared with patients on monotherapy. The responder rate for both SitDBP and SitSBP was also significantly higher in patients treated with combination therapy compared with monotherapy (35% vs 24%, p=0.032 for SitDBP and 41% vs 24%, p<0.001 for SitSBP). The relatively low normalization rates observed in this study were mainly due to the high blood pressure levels used as entry criteria. The SitSBP/SitDBP at baseline prior to randomization to combination therapy was 152 ± 11/100 ± 3 mmhg. Higher normalization rates would be expected in a patient group with lower blood pressure at baseline. The combination therapy was well tolerated. Efficacy in non responders to enalapril (Study CPL ) In a randomised, double blind study, 327 patients (in ITT population) who were non responders to enalapril (SitDBP 95 mmhg) after 2 weeks treatment with enalapril 10 mg followed by enalapril 20 mg for 4 weeks were randomised to 12 weeks treatment with either monotherapy (enalapril 20 mg) or combination therapy (enalapril 20 mg + lercanidipine 10 mg) once daily. Primary efficacy endpoint was the change from baseline in trough SitDBP (24±2h post-dose). Secondary efficacy parameters included the change from baseline in trough SitSBP and the percent of patients normalised or responders. At study end, patients on combination therapy achieved significantly greater reduction in trough SitDBP compared with monotherapy (-9.2 +/ vs / mmhg respectively, Zan-Extra PI Version 1 Page 6

7 p=0.015). The difference in SitDBP reduction between treatments was 1.8 mmhg. The significant difference between treatments was evident at week 8 and persisted through the whole treatment period. Similarly, patients on combination therapy were found to have significantly greater reduction in trough SitSBP compared with those on monotherapy (-9.8 +/ vs / mmhg respectively, p=0.013). The difference in SitSBP reduction between treatments was 3.1 mmhg. The significant difference was evident at week 4 and persisted to study end. A higher percentage of patients on combination therapy experienced normalization of SitDBP compared with patients on monotherapy (48% vs. 37%, p=0.055). Higher responder rates were also observed in patients on combination therapy for SitDBP (53% vs. 43%) and SitSBP (41% vs. 33%), even if these differences did not reach the conventional level of statistical significance (p=0.076 and p=0.116, respectively). Elderly patients Since approximately 50% of the patients in the CPL study (164/327) were at least 60 years of age, a post-hoc subgroup analysis was performed at endpoint in the subgroup aged 60 years and also in the smaller subgroup (n=101) aged 65 years: In patients aged 60 years, combination therapy showed a significantly greater decrease from baseline in trough SitDBP at endpoint compared with monotherapy (-10.9 ± 0.86 mm Hg vs ± 0.85 mm Hg, p=0.002). The decrease from baseline in trough SitSBP at endpoint was ± 1.43 mm Hg for combination therapy and -7.5 ± 1.43 mm Hg for monotherapy, p= In patients aged 65 years, a greater decrease in SitDBP and SitSBP from baseline at endpoint was seen in the combination therapy group. The treatment difference for SitDBP (3.2 mmhg) was statistically significant (p=0.044), despite the small sample size. Long term efficacy Open-label long-term extension of the randomised, double-blind add-on studies were conducted to extend treatment data up to 6 and 12 months (including the original 3 months randomised phase). In both studies the improvements in blood pressure control obtained with combination therapy during the double-blind phase of the study were maintained or increased during the long-term treatment up to 12 months duration. In non-responders to enalapril, all the 186 patients who entered the open label phase of study CPL were treated with lercanidipine 10mg / enalapril 20mg. At the last visit 60% of these patients had a SitDBP <90 mmhg and 36% a BP <140/90 mmhg. In non-responders to lercanidipine, all patients (n=221) who entered the open-label phase of study CPL were initially treated with lercanidipine 10 mg/enalapril 10 mg, but titration to lercanidipine 10 mg / enalapril 20 mg was allowed during this phase if BP remained >140/90 mmhg. At the last visit 46% of all the patients who entered the open-label extension had a SitDBP <90 mmhg and 37% a BP <140/90 mmhg. Titration occurred in 133 patients, and SitDBP (or SitSBP) normalised after titration in about 1/3 of the cases. The improvements in blood pressure control were not obtained at the expense of tolerability. INDICATIONS Treatment of hypertension. Treatment should not be initiated with these fixed dose combinations. (See Dosage and Administration) Zan-Extra PI Version 1 Page 7

8 CONTRAINDICATIONS Hypersensitivity to lercanidipine or enalapril, to any dihydropyridine calcium antagonist or ACE inhibitor, or to any of the excipients. Pregnancy (See Precautions Use in Pregnancy). Lactation (See Precautions Use in Lactation). Women of child-bearing potential unless effective contraception is used. Severe renal impairment (creatinine clearance < 30 ml/min). Severe hepatic impairment. Co-administration with cyclosporine (see Precautions - Interactions). History of angioedema whether hereditary or idiopathic, or associated with previous ACE inhibitor therapy. PRECAUTIONS Angioedema Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril maleate. In such cases Zan-Extra should be promptly discontinued and the patient carefully observed until the swelling disappears. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous adrenaline solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway should be promptly administered. (See Adverse Effects). The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months. Patients may have multiple episodes of angioedema with long symptom-free intervals. Angioedema may occur with or without urticaria. Black patients receiving ACE inhibitors have been reported to have higher incidence of angioedema compared to non-blacks. Hypotension Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of enalapril use in severely salt/volume depleted persons such as those treated vigorously with diuretics or patients on dialysis. (See Precautions, Drug Interactions and Adverse Effects.) In patients with heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotaemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the early weeks of treatment with Zan-Extra and whenever the dose of enalapril is increased. Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If hypotension occurs the patient should be placed in supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to Zan-Extra PI Version 1 Page 8

9 further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. Neutropenia/Agranulocytosis Another angiotensin converting enzyme inhibitor has been shown to cause agranulocytosis and bone marrow depression (including leucopenia/neutropenia). These reports generally involve patients who have pre-existing renal dysfunction and/or collagen vascular disease, some of whom have received concomitant immunosuppressant therapy. Most reports describe transient episodes for which a causal relationship to the ACE inhibitor could not be established. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. International marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. It is recommended that periodic haematologic monitoring be considered in patients with diseases known to affect bone marrow function (e.g., renal dysfunction, collagen vascular disease, etc.) and/or who are taking concomitant therapy known to be associated with bone marrow depression. Sick Sinus Syndrome Special care should be exercised when lercanidipine is used in patients with sick sinus syndrome (if a pacemaker is not in situ). Lercanidipine does not interfere with normal cardiac excitation and conduction when used at therapeutic dosages in patients with mild to moderate hypertension as clearly demonstrated below. Two invasive cardiac catheterisation studies were performed: Lercanidipine: a novel lipophilic dihydropyridine calcium antagonist with long duration of action and high vascular selectivity. Exp. Opin. Invest. Drugs 1999;8: ] were performed with single oral doses of lercanidipine. No evidence of reduced cardiac inotropism were found in the studies and no changes in ECG parameters, including PR and RR intervals were observed. In addition an open invasive ECG study found no negative effect on the sinus node and A-V conduction functional parameters 1.5 to 2 h after a single oral dose of lercanidipine 20 mg. A randomised, double-blind study in patients with mild to moderate hypertension was conducted to compare the effects of prolonged (2 weeks) administration of lercanidipine 20 mg once daily with those of sustained-release (SR) verapamil 240 mg once daily on cardiac excitation and conduction. The results demonstrated that lercanidipine does not intefere with normal cardiac excitation and conduction since it has no significant effect on QRS duration, or PR, QT and QTc intervals. In addition, lercanidipine had no effects on the types of cardiac arrhythmias present in these patients. The effects of lercanipine were generally similar to those of verapamil SR, although verapamil trended to prolong the PR interval. [A. Cavallini and G. Terzi; Effects of antihypertensive therapy with lercanidipine and verapamil on cardiac electrical activity in patients with hypertension: a randomised, double-blind pilot study. Curr Ther Res Clin Exp. 2000;61: (ID186)] Ischaemic heart disease It has been suggested that some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with ischaemic heart disease. Although lercanidipine is long-acting, caution is required in such patients. Outflow obstruction (aortic stenosis) Although haemodynamic controlled studies revealed no impairment of ventricular function, care is required in patients with left ventricular outflow obstruction (aortic stenosis) when treated with calcium channel blockers. Zan-Extra PI Version 1 Page 9

10 Congestive heart failure In general calcium channel blockers should be used with caution in patients with heart failure. Although animal data and acute haemodynamic evaluation in patients with preserved left ventricular function have not demonstrated that lercanidipine exerts a direct negative inotropic effect, safety in patients with congestive heart failure has not been established. Therefore as for other calcium channel blockers, lercanidipine should be used with caution in such patients, especially if untreated. Unstable angina pectoris or within one month of a myocardial infarction Rarely patients have developed documented increased frequency, duration and/or severity of angina on starting calcium channel blocker therapy or at the time of dosage increase (particularly those with severe obstructive coronary artery disease). The mechanism of this effect has not been elucidated, however the possibility of an exacerbation of angina and/or cardiac ischaemia exists. It is therefore suggested that the use of calcium channel blockers is not advisable in patients with unstable angina pectoris or recent myocardial infarction. (See Adverse Effects). Inducers of CYP3A4 Inducers of CYP3A4 like anticonvulsants (e.g., phenytoin, carbamazepine) and rifampicin may reduce lercanidipine s plasma levels and therefore the efficacy of lercanidipine may be less than expected (See Precautions - Interactions). Aortic or Mitral Valve Stenosis/Hypertrophic cardiomyopathy As with all vasodilators, ACE inhibitors should be given with caution to patients with left ventricular valvular and outflow obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction. Use in renal impairment Zan-Extra Tablets are contraindicated in patients with severe renal impairment (GFR <30mL/min)(See Dosage and Administration). Special care should be exercised when treatment is commenced in patients with mild to moderate renal impairment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients in treatment with enalapril. Renal failure has been reported in association with enalapril, mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognised promptly and treated appropriately, renal failure, when associated with enalapril therapy, is usually reversible. Some hypertensive patients, with no apparent pre-existing renal disease have developed increases in blood urea and serum creatinine, usually minor and transient especially when enalapril has been given concurrently with a diuretic. Discontinuation of the diuretic, or of Zan-Extra because of the enalapril component, may be required. This situation should raise the possibility of underlying renal artery stenosis (See Renovascular hypertension). Evaluation of the hypertensive patient should always include assessment of renal function. (See Dosage and Administration) Combination use of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists and anti-inflammatory drugs and thiazide diuretics. The use of an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist) and an antiinflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the treatment. The combination of drugs from these Zan-Extra PI Version 1 Page 10

11 three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment. Renovascular hypertension There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery due to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration and monitoring of renal function. Angioedema Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (See Contraindications). Anaphylactoid reactions during Hymenoptera desensitization Rarely, patients receiving ACE inhibitors during desensitization with hymenoptera venom (for example from, bees, ants or wasps), or during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitization or apheresis. Haemodialysis patients Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (polyacrylonitrile membranes e.g., AN 69 ) and treated concomitantly with an ACE inhibitor. These patients should be given a different type of dialysis membrane or a different class of antihypertensive agent. Hypoglycaemia Diabetic patients treated with oral antidiabetic agents should be told to closely monitor for hypoglycaemia, especially during the first month of treatment with this combination. (See Precautions - Interactions). Cough A persistent non-productive, ticklish cough has been reported in some patients undergoing treatment with enalapril and other ACE inhibiting drugs. The cough is often worse when lying down. The cough is commoner in women (who account for about two thirds of reported cases). The patients who cough may have increased bronchial reactivity compared to those who do not cough. It may disappear in some patients with continued use, or diminish or disappear if the dose of the drug is reduced. In those in whom cough persists, the drug should be discontinued. The cough usually returns on rechallenge. No residual effects have been reported. Surgery/anaesthesia In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Hyperkalaemia Elevated serum potassium (greater than 5.7 mmol/l was observed in approximately one percent of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalaemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. Risk factors for the development of hyperkalaemia may include renal Zan-Extra PI Version 1 Page 11

12 insufficiency, diabetes mellitus and the concomitant use of potassium supplements and/or potassiumcontaining salt substitutes, which should be used cautiously, if at all, with enalapril. The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium. Serum Lithium The combination of lithium and enalapril is not recommended (See Precautions - Interactions). Ethnic differences As with other ACE inhibitors, enalapril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population. (See Pharmacology.) Kidney transplantation There is no experience regarding the administration of lercanidipine or enalapril in patients with recent kidney transplantation. Treatment with Zan-Extra is therefore not recommended. (cross reference to cyclosporin use) Hepatic failure Zan-Extra is contraindicated in patients with severe hepatic impairment (See Dosage and Administration). The antihypertensive effect of lercanidipine may be enhanced in patients with hepatic impairment. Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Alcohol Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs (See Precautions - Interactions). Lactose Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/galactose malabsorption should not take this medicine. Carcinogenicity, Mutagenicity, Impairment of Fertility Further preclinical studies have not been carried out with Zan-Extra. Such data are available with the two active components. Effects on Fertility Reproductive studies in animals using the combination have not been performed. Zan-Extra PI Version 1 Page 12

13 Lercanidipine Administration of lercanidipine at oral doses up to 12 mg/kg/day (associated with exposures, based on AUC, about times the expected human exposure at 10 mg/day) had no effect on male or female fertility in rats. Enalapril There were no adverse effects on reproductive performance in male or female rats treated with enalapril mg/kg/day. Use in Pregnancy: Category D Zan-Extra is contraindicated in pregnancy (see Contraindications ). Pregnancy should be excluded before starting treatment with enalapril and avoided during treatment. If a patient intends to become pregnant while on enalapril, treatment must be discontinued and replaced by another form of treatment. If a patient becomes pregnant while on treatment, she must immediately inform her doctor to discuss a change in medication and further management. Lercanidipine There is no clinical experience with lercanidipine in pregnancy, but other dihydropyridine compounds have been found to cause irreversible malformations in animals. Therefore, lercanidipine should not be administered during pregnancy or to women of child-bearing potential unless effective contraception is used. In animal studies, pregnant rats given lercanidipine orally at doses greater than or equal to 2.5 mg/kg/day showed signs of dystocia, an increased incidence of stillbirths and a lower neonatal survival index. The no-effect dose for effects on parturition and neonatal survival was 0.5 mg/kg/day, associated with systemic exposure (AUC) similar to the expected human exposure when dosing started before pregnancy or 2.5 mg/kg/day (about 6 times the human AUC) when dosing started during early gestation. Lercanidipine doses of 2.5 mg/kg/day during gestation also caused a higher incidence of foetal visceral abnormalities (mono/bilateral renal pelvic and/or ureteric dilatation) and skeletal abnormalities (mainly delayed ossification) at all dose levels. The effects of lercanidipine during pregnancy have not been investigated adequately in a non-rodent species. Enalapril There are no adequate and well controlled studies of enalapril in pregnant women. Data, however, show that enalapril crosses the human placenta. Post-marketing experience with all ACE inhibitors suggest that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus. ACE inhibitors have also been associated with foetal death in utero. There is a potential risk of foetal hypertension, decreased birth weight and decreased renal perfusion or anuria in the foetus from in utero exposure to ACE inhibitors. Oligohydramnios in the mother has also been reported, presumably representing decreased renal function in the foetus. Any neonate exposed to enalapril in utero should be observed closely for adequate urine output, blood pressure and hyperkalaemia. If required, appropriate medical measures should be initiated including administration of fluids or dialysis to remove enalaprilat from the circulatory system. Maternal and foetal toxicity occurred in some rabbits at doses equal to or greater than 1 mg/kg/day. Saline supplementation prevented the maternal and foetal toxicity seen at doses of 3 and 10 mg/kg/day, but not at 30 mg/kg/day. Enalapril was not teratogenic in rabbits. There was no foetotoxicity or teratogenicity in rats treated with up to 200 mg/kg/day of enalapril. Foetotoxicity Zan-Extra PI Version 1 Page 13

14 shown as decreased average foetal weight, occurred in rats given 1,200 mg/kg/day of enalapril, but did not occur when these animals were supplemented with saline. Use in Lactation Zan-Extra is contraindicated in lactation (see Contraindications section). Enalapril and its active metabolite, enalaprilat, are excreted in breast milk. Lercanidipine is highly lipophilic and is expected to be excreted in human milk. Breastfeeding patients should not take Zan-Extra, or if use of the medicine is essential, breastfeeding should be discontinued. Paediatric Use Since there is no clinical experience in patients under the age of 18 years, use in children is not recommended. Use in the Elderly The dose for elderly patients should be in line with their renal function. Zan-Extra is contraindicated in severe renal impairment (creatinine clearance < 30 ml/min) or in patients on haemodialysis (see Contraindications and Precautions sections). Special care should be exercised when treatment is commenced in patients with mild to moderate impairment of kidney function. Carcinogenicity Carcinogenicity studies using the lercanidipine+enalapril combination have not been performed. Lercanidipine Carcinogenicity studies of lercanidipine administered via the diet have been performed in rats and mice (18 months), using doses up to 60 mg/kg/day for mice and 5 mg/kg/day for rats. Plasma concentrations (AUC) of lercanidipine at the highest doses were about 4-8 times the AUC expected in humans at 10 mg/day. Lercanidipine showed no evidence of carcinogenic activity in these studies. Enalapril There was no evidence of carcinogenicity when enalapril was administered to rats for 106 weeks at doses up to 90 mg/kg/day or to male and female mice for 94 weeks at doses up to 90 and 180 mg/kg/day, respectively. Several ACE inhibitors have been associated with an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential for ACE inhibitors to cause this effect in humans is unknown. The progression of oxyphilic cells to oncocytomas is rare in humans and when it does occur, it is considered benign. Genotoxicity There was no evidence of genotoxic activity for lercanidipine or enalapril. Lercanidipine did not induce gene mutation (S. typhimurium or Chinese hamster V79 fibroblasts), gene conversion (Saccharomyces ceresvisiae D4) or chromosomal damage (CHO cytogenetic assay; mouse micronucleus test). Neither enalapril maleate nor the active diacid was mutagenic in the Ames test with S. typhimurium. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E.coli, sister chromatid exchange with cultured mammalian cells, and chromosome aberration and micronucleus tests in mice. Zan-Extra PI Version 1 Page 14

15 Interactions with other Medicines The antihypertensive effect of Zan-Extra could be enhanced when associated with other antihypertensive drugs such as diuretics, beta-blockers, alpha-blockers and others. The following interactions may be observed with one or the other component of the combination. Lercanidipine Inhibitors and Inducers of CYP3A4 Since the main metabolic pathway of lercanidipine involves the enzyme CYP3A4, drugs that inhibit or induce this enzyme have the potential to alter the plasma concentration of the compound. Therefore, inhibitors of CYP3A4 (such as ketoconazole, itraconazole, erythromycin, ritonavir and fluoxetine) may increase the plasma concentration of lercanidipine, and such combinations should be used with caution. When co-administered with CYP3A4 inducers, such as anticonvulsants (eg. phenytoin, carbamazepine) and rifampicin, the antihypertensive effect of lercanidipine may be reduced and, therefore, blood pressure should be monitored when the co-administration is foreseen. CYP3A4 and CYP2D6 substrates The potential for in vivo inhibition of CYP3A4 by lercanidipine is negligible, as confirmed by an interaction study with midazolam in healthy volunteers. After repeated co-administration with lercanidipine, midazolam (a probe for CYP3A4 activity) was found to be essentially bioequivalent to the drug administered alone. However, unless specific data are available, caution should also be exercised when lercanidipine is co-prescribed with other substrates of CYP3A4 which have a narrow therapeutic index, such as cyclosporin, and class III antiarrhythmic drugs (e.g. amiodarone and quinidine). Co-administration of lercanidipine with cyclosporin resulted in a 3 fold increase in the plasma levels of lercanidipine and a 21% increase in the bioavailability of cyclosporin. However, when cyclosporin was administered 3 hours after lercanidipine, no increase in plasma levels was observed for lercanidipine, while the bioavailability of cyclosporin increased by 27%. Therefore, cyclosporin and lercanidipine should not be administered together. Moreover, interaction studies in humans have shown that lercanidipine did not modify the plasma levels of metoprolol, (a typical substrate of CYP2D6). Therefore, at therapeutic doses it is unlikely that lercanidipine will inhibit the biotransformation of drugs metabolised by CYP2D6. These findings confirm that the inhibition of cytochrome P450 isoenzymes observed in vitro with lercanidipine is devoid of any clinical significance. In vitro experiments with human liver microsomes demonstrated that lercanidipine inhibits CYP3A4 and CYP2D6 (IC 50 of 2.6 µm and 0.8 µm, respectively). The IC 50 concentrations for CYP3A4 and CYP2D6 are 160 and 40 fold higher, respectively, than those reached at peak in the plasma after a 20 mg dose. Beta-blockers When lercanidipine was administered with metoprolol, a beta-blocker eliminated mainly by the liver, the bioavailability of metoprolol was not changed, while that of lercanidipine was reduced by 50%. Therefore, when co-administered with metoprolol, it may be necessary to increase the dose of lercanidipine. It is anticipated that a similar effect may occur with propranolol. Cardiac glycosides Co-administration of lercanidipine in patients chronically treated with beta-methyldigoxin (a pro-drug of digoxin) showed no evidence of a pharmacokinetic interaction. However, patients on concomitant digoxin treatment should be closely monitored. Zan-Extra PI Version 1 Page 15

16 Cimetidine Concomitant administration of cimetidine 400 mg BD does not cause significant changes in the plasma levels of lercanidipine: AUC and C max were increased by a mean of 11%. However, at higher doses caution is required since the bioavailability and the hypotensive effect of lercanidipine may be increased. Simvastatin Co-administration of a 20 mg dose of lercanidipine with 40 mg simvastatin resulted in no increase in the bioavailability of lercanidipine, however a 56% increase was observed for simvastatin and a 28% increase for its active metabolite β-hydroxyacid. It is unlikely that these changes are clinically relevant. However, it is recommended that when required lercanidipine be administered in the morning and simvastatin in the evening. Food See previous section on pharmacokinetics. The metabolism of dihydropyridines can be inhibited by grapefruit juice, leading to increased plasma concentration and hypotensive effect. Alcohol should be avoided while taking lercanidipine since it may potentiate the effect of vasodilating antihypertensive drugs. Cyclosporin Cyclosporin and lercanidipine should not be administered together (see Interactions with CYP3A4 and CYP2D6 substrates and Contraindications). Warfarin Co-administration of lercanidipine 20 mg to fasting healthy volunteers did not alter the pharmacokinetics of warfarin. Enalapril Potassium-sparing diuretics or potassium supplements ACE inhibitors attenuate diuretic induced potassium loss. Potassium sparing diuretics (e.g., spironolactone, eplerenone, triamterene or amiloride), potassium supplements, or potassiumcontaining salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium (See Precautions). Diuretics (thiazide or loop diuretics) Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure with enalapril treatment. The possibility of hypotensive effects with enalapril can be minimised by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide medical supervision for at least one hour after the initial dose. (See Precautions, and Dosage and Administration.) Agents causing renin release The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Zan-Extra PI Version 1 Page 16